Is NHS p.Pro77Arg (c.230C>G) pathogenic?

NHS p.Pro77Arg (c.230C>G) is classified Likely benign in NHS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-01-01). Very rare (popmax 0.00024%, nfe); Associated with intellectual disability.

What condition is associated with NHS p.Pro77Arg (c.230C>G)?

NHS p.Pro77Arg (c.230C>G) is associated with intellectual disability (ClinVar).

How common is NHS p.Pro77Arg (c.230C>G) in the general population?

NHS p.Pro77Arg (c.230C>G) is very rare (popmax 0.00024%, nfe) (gnomAD).

NHS p.Pro77Arg

c.230C>G · rs2064344076 · VCV975299

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00024%, nfe)

Conditions

intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.003	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP 0.03
Regional constraint	o/e 0.79	unconstrained · MANE · 357 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	14.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00024% European (non-Finnish) · 2/833,634 alleles

Filtering AF 4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.000185% 2/1,078,202 alleles · very rare exomes 2/965,202 · genomes 0/113,000 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NHS
Protein: p.Pro77Arg
Coding: c.230C>G
MANE Select: NM_001291867
dbSNP: rs2064344076
Type: single nucleotide variant
Location: chrX:17375987 (GRCh38)
Structure: AlphaFold pLDDT 43.65
Residue 77: the 'wave homology domain (whd)' region; the 'disordered' region

Full NHS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NHS p.Gln336His Uncertain significance ★★ same condition
NHS p.Ala865Thr Benign/Likely benign ★★ same condition
NHS p.Gly1310Val Benign/Likely benign ★★ same condition
NHS p.Phe777Ser Benign/Likely benign ★★ same condition
NHS p.Thr1624Met Likely benign ★★ same condition
NHS p.Arg392Gln Conflicting classifications of pathogenicity ★ same condition
NHS p.Arg586Gln Uncertain significance ★ same condition
NHS p.Ser1125Leu Conflicting classifications of pathogenicity ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nhs-p-pro77arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown